WO2014210481A1 - Formulation polymère poreuse préparée au moyen d'agents porogènes - Google Patents

Formulation polymère poreuse préparée au moyen d'agents porogènes Download PDF

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Publication number
WO2014210481A1
WO2014210481A1 PCT/US2014/044611 US2014044611W WO2014210481A1 WO 2014210481 A1 WO2014210481 A1 WO 2014210481A1 US 2014044611 W US2014044611 W US 2014044611W WO 2014210481 A1 WO2014210481 A1 WO 2014210481A1
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Prior art keywords
copolymer
monomer
sensor according
alkyl
mixture
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PCT/US2014/044611
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English (en)
Inventor
Zenghe Liu
Jeffrey George LINHARDT
Huanfen Yao
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Google Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6813—Specially adapted to be attached to a specific body part
    • A61B5/6814—Head
    • A61B5/682—Mouth, e.g., oral cavity; tongue; Lips; Teeth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6813—Specially adapted to be attached to a specific body part
    • A61B5/6814—Head
    • A61B5/6821—Eye

Definitions

  • Electrochemical-based sensors are believed to be particularly suitable for the monitoring and quantification of analytes (e.g., glucose) in bodily fluid samples (e.g., blood, tear film, urine or interstitial fluid samples).
  • analytes e.g., glucose
  • bodily fluid samples e.g., blood, tear film, urine or interstitial fluid samples.
  • an electrochemical-based sensor that employs an analyte sensing component, (e.g., an enzyme) in conjunction with an electrode(s) allows for the quantification of an analyte in a liquid sample by detecting the product(s) produced from the reaction of the analyte sensing component and the analyte.
  • an analyte sensor in one aspect, includes a crosslinked polymer network in contact with a surface of an electrode, and an analyte sensing component immobilized within the network.
  • the polymer network includes backbone chains having first methacrylate-derived units and second methacrylate-derived units. Each first methacrylate-derived unit has a side chain, and the second methacrylate-derived units in different backbone chains are connected by crosslinks.
  • the crosslinked polymer has voids, or pores, within and defined by the network.
  • the method involves forming a solution including an analyte sensing component, one or more porogens, a limethacryiate monomer, an initiator, and a methacrylaie monomer having a side chain, depositing the mixture on a surface of an electrode, and curing the deposited mixture to provide the analyte sensor,
  • Figure 1 is a graph of current produced by an example glucose sensor at glucose concentrations of 100 ⁇ to 1,200 ⁇ . ⁇ in phosphate buffered saline (PBS). A linear relationship between current and glucose concentration was observed (see inset graph).
  • PBS phosphate buffered saline
  • an analyte sensor includes a erossJinked copolymer network in contact with a surface of an electrode, where the network includes:
  • crosslinks between the second methacrylate-derived units in different backbone chains are crosslinks between the second methacrylate-derived units in different backbone chains
  • the analyte sensor can be an enzyme-based biosensor.
  • the biosensors can be used in the detection of anaiyies in clinical, environmental, agricultural and biotechnological applications.
  • Analytes that can be measured in clinical assays of fluids of the human body include, for example, glucose, lactate, cholesterol, bilirubin and proteins, lipids and electrolytes.
  • the detection of analytes in biological fluids, such as blood, tear film, or intesiinal fluid can be imporiani in the diagnosis and ihe monitoring of many diseases.
  • the analyte sensor can be a component of a body- mountable device, such as an eye-mountable, tooth-mountable, or skin-mountable device.
  • the eye-mountable device can be configured to monitor health-related information based on one or more anaiyies detected in a tear film (the term "tear film” is used herein interchangeably with “tears” and "tear fluid") of a user wearing the eye-mountable device.
  • the eye-mountable device can be in the form of a contact lens that includes a sensor configured to detect one or more analytes (e.g., glucose).
  • the eye-mountable device can also be configured to monitor various other types of health-related information.
  • the body-mountable device may comprise a tooth- mountable device.
  • the tooth-mountable device may take the form of or be similar in form to the eye-mountable device, and be configured to detect at least one analyte in a iluid (e.g., saliva) of a user wearing the tooth-mountable device.
  • a iluid e.g., saliva
  • the body-mountabie device may comprise a skin- mountable device.
  • the skin-mountabie device may take the form of or be similar in form to the eye-mountable device, and be configured to detect at feast one analyte in a fluid (e.g., perspiration, blood, etc.) of a user wearing the skin-mountabie device.
  • a fluid e.g., perspiration, blood, etc.
  • the sensor as described herein can include one or more conductive electrodes through which current can flow.
  • the electrodes can be configured for different purposes.
  • a sensor can include a working electrode, a reference electrode, and a counter-electrode.
  • the reference electrode serves as a counter-electrode.
  • the working electrode can be connected to the reference electrode via a circuit, such as a potentiostat.
  • the electrode can be formed from any type of conductive material and can be patterned by any process that can be used for patterning such materials, such as deposition or photolithography, for example.
  • the conductive materials can be, for example, gold, platinum, palladium, titanium, carbon, copper, silver/silver-chloride, conductors formed from noble materials, metals, or any combinations of these materials. Other materials can also be envisioned.
  • the crosslinked copolymer of the analyte sensor includes backbone chains of methacrylate-derived units, and an analyte sensing component, such as an enzyme, embedded within the copolymer.
  • the first methacrylate-derived units of the backbone chains are each covalently bound to a side chain.
  • Each of the second methacrylate-derived units is covalently bound through a linker to another second methacrylate-derived unit in a different backbone chain.
  • the crosslinks, or groups rulingough which the second methacrylate-derived units are connected to each other, are discussed in greater detail below.
  • Various conformations and compositions of the side chains of the first methacrylate-derived units, and the crosslinks of the second methacry] te-derived units can he used to adjust the properties of the crosslinked copolymer as desired, which include permeability and the ability to immobilize an analyte sensing component.
  • the side chains of the first methacrylate-derived units can be water soluble or soluble in a water-miscible solvent, such as an alcohol.
  • the side chains can have one or more heteroatoms, for example, nitrogen, oxygen or sulfur atoms.
  • the side chains have one or more hydroxy groups,
  • the side chains include one or more alkylene oxide units.
  • the alkylene oxide units can be derived from ethylene oxide, propylene oxide or butylene oxide, and can be a combination of two or three different alkylene oxide units.
  • the alkene oxide units form a poly(alkylene oxide) such as pofyi ' ethylene glycol) or polyfpropylene glycol).
  • the first methacrylate-derived units can have the structure of formula (I):
  • R 1 is hydrogen, -( C !2 alkyl, -Ci-C !2 aJkyl-OH, -SiR' 3 , -C(0)-CrC i2 alkyl, -CrC i2 alkyl-C(0)OR', where R' is - ( ⁇ ( ⁇ ..alky l.
  • the first methacrylate-derived units have the structure:
  • X' is independently -0-, -NR.'- or -S-, and A is a crosslink
  • the crosslinks can be soluble in water or a water- miscible solvent, such as an alcohol.
  • the crosslinks can have one or more heteroatoms, for example, nitrogen, oxygen or sulfur atoms.
  • the crosslinks have one or more hydroxy groups.
  • the crosslinks can include one or more alkylene oxide units.
  • the alkylene oxide units can be in the form of a polymer, such as polyethylene glycol), poly(propylene glycol), polyiburylene oxide) or a mixture thereof, and can be a copolymer including a combination of two or three different alkylene oxide units.
  • the poly(alkylene oxide) of the crosslinks is a block copolymer including blocks of two or three different polyi alkylene oxide) poly mers.
  • the poly(alkyiene oxide) is a block copolymer of poly(ethylene glycol) and poly(propylene glycol).
  • the crosslinks include polyiethyfene glycol).
  • the crosslinks include one or more ethylene oxide units.
  • the crosslinks e.g., A in formula II above
  • w 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • w is an average value of from about 2 to about 250.
  • w in the crosslinks of formula (11a) is such that the number average molecular weight (Mschreib) of the PEG portion (within the brackets in formula
  • (Ha)) of the crosslinks is about 100 to about 10,000.
  • w can be selected such that the M n of the PEG portion of the crosslinks falls within a range in Table 1 :
  • the crosslinks are derived from di(ethylene glycol) dimethacrylate, i.e., compounds of formula (II) or (Ha) where X' is independently -0-, -NR'- or -S-, and w is 1.
  • the crosslinked copolymer of the anaiyte sensor can form a network having voids, which are regions within the copolymer that are not occupied by copolymer, and are referred to herein as "pores".
  • the porous network of the crosslinked copolymer can facilitate control of the equilibrium between the concentration of the anaiyte (e.g., glucose) in the sample, and ihe anaiyte concentration in the proximity of the anaiyte sensor electrode surface.
  • the measured output signal can be linearly proportional to the flow of the anaiyte and thus to the concentration of the anaiyte.
  • the measured output signal may no longer be controlled by the flow of anaiyte and may no longer be linearly- proportional to the flow or concentration of the anaiyte.
  • only a fraction of the anaiyte arriving at the anaiyte sensing component is consumed before the sensor becomes saturated, whereupon the measured signal stops increasing, or increases only slightly, with an increasing concentration of the anaiyte.
  • the porous network can reduce the flow of the anaiyte to the anaiyte sensing component so the sensor does not become saturated and can therefore enable a wider range of anaiyte concentrations to be measured.
  • the properties of the porous network can be varied to produce desired properties, such as permeability of the anaiyte. For example, flow of the anaiyte into or across the sensor can be dependent on the specific anaiyte being monitored, and thus, the porous network can be altered to obtain properties for monitoring a specific anaiyte. As discussed in further detail below, in some applications, the porosity of the porous network can be modulated by adjusting the type and/or amount of porogen used when making the anaiyte sensor.
  • the analyte sensing component is embedded, i.e., surrounded by the copolymer network of the crosslinked copolymer. The embedded analyte sensing component is immobilized and can interact with a corresponding analyte of interest. In some embodiments, the analyte sensing component includes an enzyme.
  • the analyte sensing component of the analyte sensor can be selected to monitor physiological levels of a specific analyte.
  • a specific analyte For example, glucose, lactate, cholesterol and various proteins and lipids can be found in body fluids, including, for example, tear film, and can be indicative of medical conditions that can benefit from continuous or semi- continuous monitoring.
  • the analyte sensing component can be an enzyme selected to monitor one or more analytes. For example, physiological cholesterol levels can be monitored with cholesterol oxidase, lactate levels with lactate oxidase, and glucose levels with glucose oxidase or glucose dehydrogenase (GDH).
  • physiological cholesterol levels can be monitored with cholesterol oxidase, lactate levels with lactate oxidase, and glucose levels with glucose oxidase or glucose dehydrogenase (GDH).
  • GDH glucose dehydrogenase
  • the analyte sensing component can be an enzyme that undergoes a chemical reaction with an analyte to produce detectable reaction products.
  • a copolymer including glucose oxidase (“GOx”) can be situated around the working electrode to catalyze a reaction with glucose to produce hydrogen peroxide (H 2 O 2 ).
  • H 2 O 2 hydrogen peroxide
  • the hydrogen peroxide can then be oxidized at the working electrode to releases electrons to the working electrode, which generates a current
  • the current generated by either reduction or oxidation reactions can be approximately proportionate to the reaction rate. Further, the reaction rate can be dependent on the rate of analyte molecules reaching the electrochemical sensor electrodes to fuel the reduction or oxidation reactions, either directly or catalytically through a reagent. In a steady state, where analyte molecules diffuse to the electrochemical sensor electrodes from a sampled region at approximately the same rate that additional analyte molecules diffuse to the sampled region from surrounding regions, the reaction rate can be approximately proportionate to the concentration of the analyte molecules. The current can thus provide an indication of the analyte concentration.
  • the analyte sensing component is glucose dehydrogenase (GDH).
  • GDH glucose dehydrogenase
  • the use of ODH can require the addition of a cofactor such as flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD), flavin mononucleotide, pyrroloquinoline quinone (PQQ) or a coenzyme,
  • FAD flavin adenine dinucleotide
  • NAD nicotinamide adenine dinucleotide
  • PQQ pyrroloquinoline quinone
  • the thickness of the crosslinked copolymer of the analyte sensor can vary depending on the desired properties of the analyte sensor.
  • the thickness of the copolymer as measured from the top of electrode to the top of the copolymer, can play an important role in regulating the flow of the analyte to the analyte sensing component.
  • the thickness of the copolymer can be from less than about 10 ⁇ to about 30 ⁇ .
  • the copolymer is less than 20 ⁇ in thickness, where in other applications the copolymer is about 20 urn to about 25 urn in thickness. In certain applications, the copolymer is about 10 ⁇ to about 15 ⁇ in thickness, where in other applications the copolymer is about 15 ⁇ to about 20 ⁇ or about 25 ⁇ to about 30 ⁇ in thickness. In some embodiments, the copolymer is about 20 ⁇ in thickness.
  • a method for making an analyte sensor can involve: a) forming a mixture comprising an analyte sensing component, one or more porogens, a dimethacrylate monomer, an initiator, and a methacrylate monomer having a side chain:
  • the method can further involve removing the porogen from the cured copolymer.
  • the relative amounts of the components in the mixture can vary depending on the desired properties of the resulting analyte sensor. For example, adjusting the type and/or amouni of porogen can alter the porous network of the crosslinked copolymer. Controlling the properties of the porous network can allow for the tuning of the permeability of the analyte sensor. Similar timabiiity can also be accomplished by adjusting the amount of mixture deposited on the electrode.
  • the mixture can be formed in an aqueous medium, alcoholic medium, or mixture thereof.
  • the aqueous medium can include a buffered aqueous solution, such as, for example, a solution containing citric acid, acetic acid, borate, carbonate, bicarbonate, 4-2- hydroxyeihyi- 1 -piperazineeihanesuifonic acid (HEPES), 3-
  • TAPS tris(hydroxymethy l)methyl]amino ⁇ propanesulfonic acid
  • Bicine N,N-bis(2- hydroxyethyl)glycine
  • T is tris(hydroxymethyl)methyfamine
  • T is N- rris(hydroxymethyl)meihyiglycine
  • Tricine N- rris(hydroxymethyl)meihyiglycine
  • TPASO 2-hydroxypropanesulfonic acid
  • TES ⁇ [1ris(hydroxymethyl)methyl]amino ⁇ etlianesulfonic acid
  • MOPS 3- ⁇ - morpholino)propanesulfonic acid
  • PPES piperazme-N,N'-bis(2-ethanesulfonic acid)
  • MES dimethylarsinic acid
  • SSC saline sodium citrate
  • MES 2-(N- moipholino)ethanesulfonic acid
  • MES 2-(R)-2-(methylamino)succinic acid
  • PBS phosphate buffered saline
  • the mixture is formed in a mixture of a buffered aqueous solution and ethanol.
  • the percentage of each component can be varied in the mixture.
  • the percentage of analyte sensing component in the mixture is about 20 % by weight to about 50 % by weight
  • the percentage of porogen is 1 % by weight to about 30 % by weight
  • the percentage of fsrst methacrylate monomer is about 30 % by weight to about 60 % by weight. All percentages are given as a percentage of the cumulative amount of analyte sensing component, porogen and first methacrylate monomer.
  • the percentage of analyte sensing component is about 40 %
  • the amount of porogen is about 10 %
  • the amount of first methacrylate monomer is about 50 %.
  • the mixture is thoroughly mixed, optionally with a stirrer or shaker, before being deposited onto a surface of an electrode.
  • the mixture can be formed by combining indi vidual solutions containing the components of the mixture.
  • the method can involve:
  • the first, second and third solutions of the method are formed with approximately the same concentration of analyte sensing component, porogen, methacrylate monomer, respectively.
  • the percentage of each component can then be varied by adjusting the amounts each solution used to form the mixture.
  • the mixture can be formed on a surface of an electrode.
  • each component or a combination of one or more components, can be individually deposited to form the mixture.
  • the solutions can combined on a surface of an electrode to form the mixture.
  • the analyte sensing component can be selected based on the analyte desired to be monitored. For example, to monitor physiological cholesterol levels, cholesterol oxidase can be used, and to monitor lactate levels lactate oxidase can be used. To monitor glucose levels, the analyte sensing component can include glucose oxidase or glucose dehydrogenase (GDH).
  • GDH glucose dehydrogenase
  • the analyte sensing component can be present during polymerization of the methacrylate and dimethacrylate monomers in the deposited mixture, such that polymerization of the methacrylate and dimethacrylate monomers results in the formation of a crosslinked copolymer network in which the analyte sensing component is embedded.
  • the embedded analyte sensing component is immobilized and can be used to monitor a corresponding analyte of interest.
  • the porogen is selected for properties that will allow for the removal of the porogen from the copolymer to fonn the pores of the copolymer network.
  • the porogen can be water-soluble, nontoxic and biocompatible.
  • the porogen can also have a structural size that enables the formation of pores that are not too small to let the analyte pass through, but not large enough to let the embedded analyte sensing component to leach out of the copolymer network. The range of porogen sizes can therefore be dependent on the analyte and/or the analyte sensing component used in the sensor.
  • the porogen is a salt, such as a water-soluble organic or inorganic salt.
  • Organic salts can be Group 1 (e.g., Li, Na, K, Cs) or Group 2 (e.g., Mg, Ca, Sr, Ba) salts of carboxylic acids, such as monosodium glutamate.
  • Group 1 or 2 salts of carbonate (CO 3 ) 2" , bicarbonate (HCO 3 ) " , and phosphate (PO 4 ) inorganic salts include any combination of cations from the Group 1 or 2 elements with anions from the Group 17 elements (e.g., F, CI, Br, I).
  • the salt is NaCl,
  • the porogen is a water-soluble polymer.
  • water-soluble polymers include poly(alkylene oxide), polyvinyl alcohol), poiyacrylamide, sodium polyacrylate, lithium polyacrylate, potassium poiyacrylate, ammonium polyacrylate and poly(N-vinyl pyrolidone).
  • Poly(a3kylene oxide) polymers that can be used as a porogen in the method include poly(ethy3ene glycol), poiy(propylene glycol), poly(butylene oxide) or a mixture thereof.
  • Alkylene oxide copolymers including a combination of two or three different alkylene oxide units can also be used as porogens in the method.
  • the porogen is poly(ethylene glycol) (PEG).
  • PEG poly(ethylene glycol)
  • M n number average molecular weight
  • the porogen is a sugar, which can be a monosaccharide, disaccharide, oligosaccharide, polysaccharide or amino sugar.
  • Monosaccharides that can be used as a porogen in the method include glucose (dextrose), fructose(ievulose), galactose, xylose and ribose.
  • Monosaccharides can be used as porogens is their acyclic, pyranose or furanose forms, or a mixture thereof.
  • Disaccharides include sucrose, lactose, and maltose, lactulose, trehalose and cellobiose.
  • Oligosaccharides are saccharide polymers containing a small number (two to ten) of monosaccharide units.
  • Polysaccharides are saccharide polymers containing a large number (ten or more) of monosaccharide units.
  • Oligosaccharide and polysaccharide porogens as used in the method include water-soluble oligomers and water- soluble polymers of glucose, fructose, galactose, xylose or ribose.
  • Amino sugar porogens include a sugar having a nitrogen atom, such as N-acetyl glucosamine, galactosamine, glucosamine, sialic acid and L-daunosamine.
  • the porogen can be a salt, a water-soluble polymer, a sugar or any mixture thereof,
  • the first methacrylate monomer has side chains that can have one or more heteroatoms. m certain embodiments, the side chains are selected to form the crossiinked copolymer of the analyte sensor as described herein,
  • the methacrylate monomer has the structure of formula (III):
  • X, y, R , and R' are selected to provide the first methacrylate-derived niononieric unit of the crossiinked copolymer described herein.
  • the methacrylate monomer has the structure:
  • the dimethacrylate monomer is a molecule having two terminal methacrylate groups tethered by a linker.
  • the linker is selected to provide the crosslinks between the second methacrylate-derived units in different backbone chains of the crossiinked copolymer described herein.
  • the extent of crosslinking in crossiinked copolymer of the analyte sensor can be controlled by adjusting the amount of dimethacrylate monomer in the mixtitre.
  • the dimethacrylate monomer is about 0.1 % to about 15 % of the mixture.
  • the amount is about 1 % to about 5 %, or about 5 % to about 10 %, or about 10 % to about 15 % of the mixture.
  • the amount is about 1 %.
  • the mixture includes about 1% of the dimethacrylate monomer.
  • the dimethacrylate monomer includes one or more aikvlene oxide units to pro vide the crosslinks of the crosslinked copolymer described herein.
  • the dimethacrylate monomer includes poly(ethyleiie glycol) (PEG).
  • PEG poly(ethyleiie glycol)
  • the dimethacrylate monomer can have the structure of formula (IV):
  • w 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the dimethacrylate monomer can have the structure of formula (IV) where w is such that the number average molecular weight (M n ) of the PEG portion of the dimethacrylate monomer is about 100 to about 10,000.
  • w can be selected such that the M- of the PEG portion of dimethacrylate monomer falls within a range in Table 1.
  • the dimethacrylate monomer is di(ethylene glycol) dimethacrylate.
  • Depositing the mixture onto a surface of an electrode can be accomplished by a number of methods.
  • the depositing can be performed manually with a micro- syringe, or by automated fabrication processes with nano-jet dispensing equipment.
  • the amount of mixture deposited onto a surface of an electrode is selected to provide the desired thickness of the crosslinked copolymer of the analyte sensor.
  • the amount deposited on the electrode is about 50 nL/mm' to about 500 nL mm 2 .
  • the amount is about 50 nL/mm 2 to about 150 nL/mm 2 , or about 150 iiL/mm ' to about 300 nL/mm", or about 300 nL/mm 2 to about 500 nL/mm 2 .
  • the amount is about 100 nL/mm'.
  • about 100 nL/mm 2 of the mixture is deposited on the electrode and cured to provide a crosslmked copolymer that is about 20 ⁇ in thickness.
  • Conditions suitable to initiate polymerization can be selected based on the characteristics of the initiator and the monomers being polymerized, but not to degrade the analyte sensing component.
  • the analyte sensing component is an enzyme
  • the temperature and pH of the method can be selected to preserve the activity of the enzyme.
  • the initiator is activated with ultraviolet (LTV) light.
  • LTV ultraviolet
  • the curing can be performed with UV light
  • the porogen can be removed, for example, by washing the cured copolymer with an aqueous solution.
  • the properties of the aqueous solution can be selected based on the porogen used in the method, in some examples, the aqueous solution is water or buffered water (e.g., PBS). In other instances, the porogen is removed with an acidic (pH ⁇ 7) solution or a basic (pH >7) solution.
  • the aqueous solution includes an alcohol, such as ethanol.
  • the aqueous solution includes a water miscible organic solvent, such as tetrahydrofuran (THF).
  • Example 1 Immobilization of GOx in a Porous, Crosslinkcd Methacrylate Copolymer.
  • Example 1 The analyte sensor formed in Example 1 was tesied at concentrations of glucose in phosphate buffered saline (PBS) ranging from 100 ⁇ . ⁇ to 1,200 ⁇ . The sensor was submerged in PBS and the glucose concentration was increased every 2-7 minutes. The current generated at the electrode was measured using a potentiostai ( See Figure 1). A linear relationship between current and glucose concentration was observed (See inset, Figure 1).
  • PBS phosphate buffered saline
  • crosslinked polymer networks in the above examples comprise methacrylate groups, there are a number of ethytemcaily unsaturated groups known in the art to be capable of undergoing polymerization.
  • Ethylenically unsaturated monomers and macromers may be either acrylic- or vinyl-containing.
  • Acrylic -containing monomers are represented by the formula:
  • suitable polynierizable groups may include acrylic-, ethacrylic-, itaconic-, styryl-, acrylamido-, methacrylamido- and vinyl-containing groups such as the ally! group,
  • crosslmked polymer networks by the polymerization of ethylenically unsaturated monomers and macromonomers
  • additional chemistries will be known to one or ordinary skill in the art to from such networks.
  • epoxy chemistry in which multifunctional amines and multifunctional epoxy compounds are mixed together and cured, can be used to form cross-linked polymer networks.
  • urethane chemistry may be used, in which multifunctional isocyanates are mixed with multifunctional alcohols and cured to provide cross-linked polymer networks.
  • Other chemistries for the formation of cross-linked polymer networks exist, and will be well known to those of ordinary skill in the art.
  • some embodiments may include privacy controls which may be automatically implemented or controlled by the wearer of a body-mountable device. For example, where a wearer's collected physiological parameter data and health state data are uploaded to a cloud computing network for trend analysis by a clinician, the data may be treated in one or more ways before it is stored or used, so that personally identifiable information is removed. For example, a user's identity may be treated so that no personally identifiable information can be determined for the user, or a user's geographic location may ⁇ be generalized where location information is obtained (such as to a city, ZIP code, or state level), so that a particular location of a user cannot be determined.
  • wearers of a body-mountable device may be provided with an opportunity to control whether or how the device collects information about the wearer (e.g., information about a user's medical history, social actions or activities, profession, a user's preferences, or a user's current location), or to control how such information may be used.
  • the wearer may have control over how information is coliected about him or her and used by a clinician or physician or other user of the data.
  • a wearer may elect that data, such as health state and physiological parameters, collected from his or her device may only be used for generating an individual baseline and recommendations in response to collection and comparison of his or her own data and may not be used in generating a population baseline or for use in population correlation studies.

Abstract

L'invention concerne un capteur d'analyte destiné à la surveillance continue ou semi-continue de paramètres physiologiques, et un procédé de fabrication de ce capteur d'analyte. Le capteur d'analyte comprend un réseau copolymère réticulé en contact avec une surface d'une électrode. Le réseau copolymère comporte des vides formés par le retrait d'un agent porogène, et un composant de détection d'analyte est immobilisé dans le réseau. Le procédé consiste à former une solution des précurseurs du copolymère, déposer le mélange sur une surface d'une électrode et durcir le mélange déposé pour obtenir le capteur d'analyte.
PCT/US2014/044611 2013-06-28 2014-06-27 Formulation polymère poreuse préparée au moyen d'agents porogènes WO2014210481A1 (fr)

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US13/930,877 US9750445B2 (en) 2013-06-28 2013-06-28 Porous polymeric formulation prepared using porogens
US13/930,877 2013-06-28

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